Angiogenesis (new blood vessel formation) is a critical step for tumor growth and metastasis, and its inhibition is currently the most promising approach for cancer therapy. Contortrostatin (ON) is a protein isolated from southern copperhead snake venom, which has been shown to effectively block angiogenesis, as well as metastasis. The potent inhibitory effect of CN on cancer progression has been proven in animal models of several types of cancer. However, two problems hinder its clinical application. First, ON is recognized by the human immune system as a foreign protein. Therefore, repetitive delivery of ON to patients induces the production of antibodies that neutralize its activity. Second, ON is eliminated from the circulation too quickly to exert a sustained effect. We propose to circumvent these obstacles by making an antibody to the ON antibody (antiidiotype) that will mimic the anti-cancer activity of native ON. This ON surrogate can then be genetically modified to resemble a human antibody (humanized), which will evade rejection by the immune system. The life span of this 'humanized" antibody in circulation will be similar to native immunoglobulin and thus ideal for long-term therapy. This project should result in a biopharmaceutical lead for antiangiogenic therapy. PROPOSED COMMERCIAL APPLICATION: In 1999, the NIH designated the development of antiangiogenic therapies for cancer as a national priority. About two dozen antiangiogenic drugs have entered clinical trials, and some cancer patients have experienced dramatic regression or stabilization of their tumor from antiangiogen therapy. Yet, none of these antiangiogenic drugs have been approved by FDA. According to the Angiogenesis Foundation, diseases that may be treatable with angiogenesis-based drugs encompass markets representing 20% of the $322 billion global pharmaceutical market.